This research will be done primarily in Argentina in the Division Medicina Experimental, Academia Nacional de Medicina, in collaboration with Dr. Isabel Piazzon as an extension of NIH grant #P01 CA77760. We have been using mouse mammary tumor virus (MMTV), a retrovirus that causes mammary tumors in mice, to study virus/host interactions. MMTV is an excellent model system for the study of mucosally-acquired viruses, since it is transmitted through milk to neonatal suckling pups, infects lymphocytes in the Peyer's patches and uses these cells to spread in the animal. Our studies have focused on understanding the mechanisms which determine genetic susceptibility to MMTV infection in vivo, using different inbred, transgenic and knockout mice. This approach has led to identification of many of the steps that MMTV uses in vivo to take advantage of its host, as well an understanding of how this virus interacts with cells of the immune system. In the next funding period, we will continue to use genetic approaches to study genes that affect the interaction of MMTV with dendritic cells in the Peyer's patches. We will study the role of a family of receptors involved in innate immunity, the toll-like receptors (TLR), that we have recently shown are involved in an early step in the MMTV infection pathway, stimulation of B cells. Since dendritic cells have also been implicated in MMTV infection and are known to be one of the primary mediators of innate immune responses, understanding their role in virus infection is likely to provide insight into virus/host interactions.